TTP AND RELATED PROTEINS IN INFLAMMATORY DISEASES

炎症性疾病中的 TTP 和相关蛋白质

• 批准号: 6290085
• 负责人: Perry J Blackshear
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290085
• 关键词: chemical stability; gene targeting; inflammation; laboratory mouse; messenger RNA; pathologic process; protein structure; tumor necrosis factor alpha

One major area of study in the laboratory began with the cloning of a gene that was rapidly induced by insulin. The protein encoded by this gene, known as TTP, is the prototype of a novel class of CCCH zinc finger proteins. TTP is rapidly induced, translocated from the nucleus to the cytosol, and phosphorylated on serine residues by insulin and by many other mitogens and growth factors. Mice deficient in this protein develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death; more recent work has identified an excess of tumor necrosis factor (TNF)as the cause of most if not all aspects of the syndrome. TNF is over-produced by macrophages derived from these knockout mice, due to an increase in the stability of its mRNA. We recently determined that TTP caused instability of TNF by binding directly to its mRNA, leading in some way to its rapid degradation. Current studies are attempting to determine the mechanisms of this effect, as well as attempts to utilize this novel pathway regulating TNF expression as a target for new drugs for the treatment of TNF excess diseases, such as rheumatoid arthritis, Crohns disease, AIDS, cancer and others. - tumor necrosis factor; rheumatoid arthritis; cancer; AIDS; Crohn's disease; mRNA stability; knockout mice; zinc finger proteins

实验室中的一个主要研究领域始于胰岛素迅速诱导的基因的克隆。该基因编码的蛋白质（称为TTP）是新型CCCH锌指蛋白的原型。 TTP迅速诱导，从细胞核转移到细胞质，并通过胰岛素以及许多其他有丝分裂剂和生长因子在丝氨酸残基上磷酸化。缺乏这种蛋白质的小鼠会形成一种复杂的综合征，该综合征由关节炎，浪费，皮炎和早期死亡组成。最近的工作已经确定过多的肿瘤坏死因子（TNF）是综合征的大多数情况的原因。由于其mRNA的稳定性提高，TNF由这些敲除小鼠产生的巨噬细胞过多。我们最近确定TTP通过直接与其mRNA结合而导致了TNF的不稳定性，以某种方式导致其快速降解。当前的研究正在尝试确定这种作用的机制，并试图利用这种调节TNF表达的新途径作为治疗TNF多余疾病的新药物的靶标，例如类风湿关节炎，克罗恩斯疾病，艾滋病，艾滋病，癌症。 - 肿瘤坏死因子；类风湿关节炎;癌症;艾滋病;克罗恩病； mRNA稳定性；淘汰小鼠；锌指蛋白